Compounds having a heterocyclic group and a diamine structure are known to be useful as preventive/therapeutic drugs for a variety of thrombus-related diseases, because they exhibit excellent inhibitory action against an activated coagulation factor (FXa) (Patent Documents 1 to 6, and others). For introducing a heterocyclic group into any of the above compounds, the compound of formula (5); i.e., 5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine-2-carboxylic acid (hereinafter referred to as compound (5)):
is an important intermediate.
In one process which has hitherto been known to produce compound (5), a piperidone derivative is treated with phosphorus sulfide to thereby form a thiazole ring, and then, a methyl group is introduced to the 5-position by use of lithium aluminum hydride, and the 2-position is converted to a lithium salt of carboxylic acid (see, for example, Patent Document 7). In another known process, a mercapto group which has been introduced into a protected aminopyridine is subjected to a ring formation reaction, followed by chemical reduction of the pyridine ring to thereby form a lithium salt of carboxylic acid (see, for example, Patent Document 1). In yet another known process, protected piperidone is first transformed into 2-amino-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine (hereinafter referred to as compound (2)) in the presence of a secondary amine by use of sulfur powder and cyanamide, then brominated with copper bromide(II) and alkyl nitrite, after which a methyl group is introduced to the 5-position by use of formaldehyde and triacetoxysodium borohydride, and the resultant 2-bromo-5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine (hereinafter referred to as compound (3)) is transformed to a lithium salt of carboxylic acid (see, for example, Patent Document 1).
However, any of the above methods involves reactions that are difficult to manipulate when performed on an industrial scale, and includes a considerable number of steps because protection/deprotection steps are needed. Moreover, since chromatography is employed for purification, the overall production time is extended, which is industrially disadvantageous. Also, a compound (5) isolated as a lithium salt is highly hygroscopic, and therefore handling is difficult. Moreover, since the compound (5) lacks stability, storage-related problems arise.
In the meantime, compound (2) has been known to be obtained by reacting 1-methyl-4-piperidone (hereinafter referred to as compound (1)) with bromine (see for example, Patent Document 8).
However, use of bromine is industrially disadvantageous, as it is difficult to handle and places a great load on the environment. Moreover, during the process, a brominated compound must be isolated as an intermediate, which means that the process requires two steps.
Another method which has been known for preparing a compound (3) includes bromination of compound (2) with copper bromide (II) (see, for example, Patent Document 9). However, this method requires copper bromide (II) in an amount equal to or more than that of the compound (2). This makes it difficult to separate by-produced copper salts after the reaction, and chromatography is needed for purifying compound (3). Thus, the method is industrially disadvantageous.
[Patent Document 1] International Publication WO 01/74774 pamphlet
[Patent Document 2] International Publication WO 03/000680 pamphlet
[Patent Document 3] International Publication WO 03/016302 pamphlet
[Patent Document 4] International Publication WO 2004/058715 pamphlet
[Patent Document 5] International Publication WO 2004/058728 pamphlet
[Patent Document 6] International Publication WO 03/000657 pamphlet
[Patent Document 7] International Publication WO 01/62763 pamphlet
[Patent Document 8] Netherlands patent No. 6610324
[Patent Document 9] International Publication WO 92/07849 pamphlet